Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System

• Published in: Cancers Vol. 13; no. 24; p. 6334
• Main Authors: Montesinos-Rongen, Manuel, Brunn, Anna, Sanchez-Ruiz, Monica, Küppers, Ralf, Siebert, Reiner, Deckert, Martina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.12.2021; MDPI
• Subjects: Affinity; Antigens; Apoptosis; B-cell lymphoma; B-cell receptor; Bcl-6 protein; BCR-ABL protein; Biopsy; BTG2 protein; Cell differentiation; Cell proliferation; Central nervous system; Classification; Epigenetics; Epstein-Barr virus; Genomes; Genomic instability; Germinal centers; Hypotheses; Immunocompetence; Immunoglobulin M; Immunological memory; Independent study; Lymphocytes B; Lymphoma; Major histocompatibility complex; Medical prognosis; Memory cells; Morphology; Mutation; Myc protein; MyD88 protein; Nervous system; NF-κB protein; Pathogenesis; Pax5 protein; Review; Somatic hypermutation; Translocation; Tropism; Tumor cells; microenvironment; mouse; PCNSL; somatic hypermutation; diffuse large B cell lymphoma; CNS; germinal center; B cell receptor; animal model; molecular pathogenesis
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13246334

Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-κB signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL.